Industry Watch Blog

JUNE 2018

The Future of Excipients

Most excipients have been commonly used for more than fifty years and are still used today. There have been no major alterations made to the excipients specification over the years. There has been no debate about what would occur when our current excipients and/or their specifications are not sustained with the relevant requirements to ensure efficient medicines can be formulated, developed and manufactured on a regular basis. Change is happening.

WE are now in a new era, which consists of the arrival of combinatorial chemistry, high-throughput screening, recombinant technologies and along with better insights of proteins, drug receptor interactions, monoclonal antibodies. Also, we have very advanced tools which allow us to uncover very effective drugs. The innovation of excipients cannot adapt to the drug discovery developments.

Most excipients may be considered as inadequate regarding meeting certain industry requirements. Few excipients do not have satisfactory test methods in place to detect adulteration. This raises a few questions for regulatory agencies, as it is their duty to protect the public from contaminated medicines. Understanding of some excipients is too low to develop strong formulations for some drug molecules. The specifications are not strict enough to ensure that it can be used for the manufacturing of some drug products.

The pharmacopoeias have established more defined monograph specifications over the past few years. This was supported by the partnership of the Pharmacopoeial Discussion Group (PDG) to react to some of the controversies and adversities associated with the official substances (and food items) in recent years which consists of contaminated glycerine in Hati and other countries (ethylene glycol and diethylene glycol), contaminated heparin in Germany and the US (over-sulfated chondroitin sulfate), and contaminated milk in China (melamine). The FDA has requested the United States Pharmacopoeia-National Formulary (USP-NF) to modify all monographs, which consists of a particular identity test (id test) for every official substances, includes excipients. A priority list of excipients has been acknowledged, which does not involve a particular id. test and the analysis are not specific, thus leaving a substance which could easily be contaminated. The USP-NF Expert committees continue to investigate this matter further.

Biotechnology drug formulation (e.g. peptides, proteins and monoclonal antibodies). Biotechnology drug products formulation outlines various requests based on the interpretation and control of the composition of the required excipients.This represents various issues for the formulator (excipient user) and the excipient manufacturer. Excipient users require more information and stricter specifications for the elements involved in the excipient. The manufacturer must assess how to deliver this at an effective cost and without interfering with the excipients performance, which is required by their customers. It must be noted that most excipients are manufactured through continuous processing in large quantities. Pharmaceutical use may be below 10% of the manufacturer’s total output, and the implementation for parental products may be below 10% of the pharmaceutical use, which only requires a very small usage.

User’s requirements (preferred specification requirements) for excipients are applied in the formulation and manufacture of biotechnology drug products may be exceeding the proficiencies of the manufacturing stages and raw material sources. How can we address this evident impasse? It is determined by the excipient in question. A certain amount of excipients may be amenable to simple purification methods. Others may demand the purification of raw materials and reagents before synthesis occurs. However, others may request further safety measures to be carried out beyond the purified starting materials and reagents, for example preventing the formation of by-products, etc. All of these implications have additional financial cost. Biotechnology products usually have a very high price, due to excipients being expensive. The excipient cost per unit is decreased, due to the small quantities used per unit dose.

It is evident that new ideas are necessary for the use, tracking and procurement of excipients for the manufacture of bio-technology developed drug products. There is the possibility that there are particular (enhanced purity or super-refined) grades of some excipients, which should be examined. These grades would have decreased levels of concomitant components. On the other hand, it may mot be easy to develop and introduce to the market. Small quantities are necessary. It is not straightforward to implement this manufacture type on a manufacturing plant, which was constructed to produce ‘000’s of tonnes per annum. The enhanced purity grade may not be suitable for every user as the concurrent components available in the traditional grade may be required for excipient and/or product operations in other applications.

The pharmacopoeias issue should be taken into account. A segment of its existing aims of pharmacopoeia is to reinforce the monographs as it is predominately associated with the detection of adulteration. How do they integrate improved purity grades into a monograph for a specific material? Do these cases provide a potential opportunity?

Let’s take vegetable fixed oils for example. Fatty acid composition alone is not enough to determine contamination, however when it is integrated with sterol composition, they collaborate with one another. This improved purity grades will possibly have a changed fatty acid composition and a decreased content of sterols. Will the criteria of the amalgamated tests be enough to determine contaminated at an adequately low level?

The fixed oils may not be applicable to the formulation of the majority of biotechnology drug products, but fatty acids and related issues apply.

What is the ideal time-frame to wait before; they are applied in a pharmaceutical finished product? How do we integrate them into pharmacopoeias? Must a separate monograph be created or must we explore other options to integrate them into its existing monograph? The time has come for pharmaceutical and biopharmaceutical manufacturers to take excipients seriously.

A&C are at the forefront of custom excipients with full product documentation. The good news is that there are changes with the excipient marketplace. This shows how pharmaceuticals and biopharmaceuticals can reduce costs efficiently.

JUNE 2018

The Development of New Vaccines for Future Generations?

Nowadays, there are many diseases emerging. As a result, there are new types of vaccines being developed to combat these diseases which could potentially occur for future generations.

Bill Gates has collaborated with Google co-founder Larry Page, to allocate funding for the development of a universal flu vaccine.

Although, there were attempts to create a universal vaccine which combats all types of flu, Bill Gates has questioned scientists to explore other avenues. He requested them to create a vaccine which will combat current and emerging forms of diseases for three to five years.

The deadliest flu pandemic happened 100 years ago. Since then, there were numerous flu pandemics which killed almost 18,000 people in 2009. This is estimated to reach more than 284,000.

Bill Gates declared at the end of April “This should concern us all, because if history has taught us anything, it’s that there will be another deadly global pandemic”.

Despite the ability of annual flu vaccination to save lives, it is ineffective compared to other vaccines. Flu vaccines are roughly speaking 40% to 60% successful in contrast to similar models of MDR, which achieved a high 97% rate. This is due to the fast alteration of flu variations which develops and manufactures new vaccines over time.

Developing vaccines towards flu is very difficult to determine. Scientists now must encounter several challenging diseases and conditions than ever before, which consists of malaria, cancer, AIDs and Alzheimer’s. Some diseases which consist of Zika and Ebola can spread quicker than we can develop new vaccines.

There are a few new developments in vaccines.

A New Type of Vaccine

There are more innovative ways to manufacturing new vaccines in demand, which consists of implementing more effective techniques of vaccine propagation.

For example, cell-based flu vaccines have been recognized as a substitute to traditional egg-based vaccines. These vaccines are quicker and easier to manufacture to address issues associated with egg allergies. Please refer to http://acggp.com/industry-watch-blog/ for our previous Industry blog post on cell-based flu vaccine.

Egg-based flu vaccines have been condemned for its incompetency for many reasons, which includes post antibody-antigen binding affinity.

Live recombinant vaccines employ attenuated viruses (or bacterial strains) as vectors for immunogens which acts as a substitute. Recombinant vaccines are faster to manufacture and more efficient and have very little adverse effects compared to traditional substitutes.

Recombinant and cell-based vaccines are more appropriate to reacting to a pandemic, due to its ability to be manufactured faster.

DNA vaccines are a potential opportunity for R&D development. DNA vaccines remove the DNA which encodes a specific antigen and injects it directly into the muscle or skin.

DNA vaccines are simple to manufacture and deliver long-term immunity with very little adverse effects. They are inexpensive compared to other vaccines and convenient to transport which helps to meet the requirements of those in developing countries.

DNA vaccines have not yet been discovered to create a immune response which is very effective to facilitate further development requirements in this area. Adjuvants support DNS to enter cells or aim it towards particular cells could be suggested to help the efficacy of vaccines.

Investigating New Vaccine Delivery Methods

There are several ways to deliver future vaccines.

Nasal sprays have been implemented as a pain-free way to distribute the flu vaccine to children and introduce other pain-free vaccines in the future.

Patches which releases vaccines through a matrix of very small needles are one part of a substitute in this development. They are not required to be distributed by a healthcare professional which makes them ideal for use in remote districts.

Vaccines which overcome the cold-chain issue are required. Numerous vaccines are required to be stored at cold temperatures to stay viable which could cause some issues when delivering them. The Icelandic volcano Eyjafjallajokull erupted in 2010 resulted in planes being grounded which transported 15 million doses of polio vaccine, which raised concerns regarding the disease spreading.

In-depth Understanding of the Immune System

It is necessary to understand the workings of the immune system, in order to develop new vaccines. Developments in key areas which consists of genomics, bioinformatics and artificial intelligence can support scientists discover the challenges associated with the immune system and create more ground-breaking vaccines.

Even though, developing new vaccines may prove demanding, it has the ability to save millions of lives throughout the world which makes it more meaningful.

MAY 2018

Under pressure — how to get the best out of process R&D

Process R&D is vital in the development of pharmaceuticals and therapies yet more and more companies are being put under pressure to reduce time, costs and risk associated with process R&D to make treatments widely available and accessible to patients.

Pharmaceutical process research and development (R&D) is indispensable in the development of personalized medicines and innovative treatments that deal effectively with diseases. In order to make treatments widely available and accessible to patients, the pressure to demonstrate improved outcomes at lower costs is getting higher. This is particularly true when Europe faces increasing competition from emerging economies, such as Brazil and China.

This is where contract research and development organizations (CDMOs) can play a critical role in helping drug makers develop competitive processes without patent infringement risks and short time-to-market. But first things first…

Process R&D

Process R&D in the pharmaceutical industry has a long list of criteria that must be considered. These include optimal route of synthesis selection, availability of starting materials, prior art and the intellectual property landscape, quality criteria and regulatory hurdles, chemical safety concerns, toxicity and environmental sustainability, to name only a few.

Optimal process R&D is critical as it can save significant expenses for the pharmaceutical industry. How? By devising new concepts, employing novel methodologies and using upcoming technologies that can reduce total chemical steps, ensure product quality and safety, guarantee consistent yields and delivery timelines, as well as reduce waste.

Prior at route of synthesis (ROS)

Designing competitive and IP-free ROSs as a way of controlling costs of materials and manufacturing is an endeavour of creativity and inventiveness. It takes meticulous work and resources to demonstrate and sustain the competitive advantage, avoid patent infringement risks and still be in line with product launch timelines.

Raw materials

Proper selection of raw materials can have a major impact on the overall cost of the chemical process development. Whether it is about making drastic improvements in the properties of existing substances or developing new synthetic ones, optimal selection, sourcing, quality control and effective management of raw materials can lead to shorter, greener and scalable processes.

Lean manufacturing processes

Designing seamless and sustainable manufacturing processes can deliver enormous benefits in terms of resource efficiency, product quality and competitiveness. Improved manufacturing processes can ensure process repeatability and scalability,3as well as generate less waste and enhance sustainability. This can be done with more efficient chemical pathways and/or catalysts, advanced process control strategies and the implementation of new reaction and separation technologies and concepts.

Geography does matter

Many CDMOs are shifting their R&D units to smaller cities where operational and workforce costs are lower, and where academic communities and high scientific output can offer fresh perspectives, stimulate new thinking and bring them closer to cutting-edge R&D solutions.

MAY 2018

Formulating Topical Products Containing Live Microorganisms as the Active Ingredient

In recent years, many topical probiotic personal care products have been launched into the market (1). In an August 2016 review for Dermatology Times (2), dermatologist Patricia Farris concluded, “The studies reviewed suggest that topical prebiotics, probiotics, and bacterial cell lysates do provide demonstrable skin benefits …At this time, it appears that more studies are warranted to determine if these products are really worth the hype.” These scientific reviews are quick to point out that well-crafted, vehicle-controlled clinical trial results are not generally available for topical semisolids containing live microorganisms. One reason that topical probiotic therapies have not advanced beyond the personal care “post-marketing surveillance regulatory environment” into the controlled clinical trial “new drug approval regulatory environment” is the difficulty in reconciling FDA microbiological requirements for a product containing live microorganisms. More specifically, how can a topical suspension containing more than 50,000 colony forming units (CFU) of probiotic active pharmaceutical ingredient (API) pass United States Pharmacopeia (USP) microbial enumeration testing (USP <61>) (3), tests for specified organisms (USP <62>) (4), and antimicrobial preservative effectiveness (USP <51>) (5)?

Two case studies are being presented here to explore the strategy of adequately preserving the formulation, but using a preservative of sufficiently narrow spectrum to maintain viability/potency of the probiotic active. The first case study uses a probiotic strain of Propionibacterium acnes (P. acnes). P. acnes is a lipophilic, gram-positive anaerobic bacillus that resides in the pilosebaceous unit of human skin. Hundreds of different strains of P. acnesexist. The lipases, proteases, and hyaluronidases secreted by certain strains of P. acnes injure the lining of the pilosebaceous unit and activate production of proinflammatory cytokines that in turn lead to acne vulgaris. Other strains of P. acnes produce no inflammatory response and thus do not induce the symptoms of acne vulgaris. One of these non-inflammatory strains of P. acneshas been chosen to be used as an “active ingredient” in a topical formulation product. In the second case study, the microorganism is a bacteriophage (phage), which is a virus that infects and replicates within a bacterium, ultimately causing bacterial death. The phage used in this study was isolated from the follicular casts obtained from volunteers with facial comedones. Bacteriophages were identified and isolated from the comedones and were then propagated using an amplification process and plated against different P. acnes strains to determine breadth of efficacy to assure the selected phage was suitable to infect and eradicate pathogenic (inflammatory) P. acnes strains.

Formulating a living microorganism is fundamentally different from formulating a small-molecule active topical product. Because the P. acnes probiotic or phage products will be dosed as suspensions, active solubility, solvent compatibility, and penetration across the stratum corneum do not factor in to the development of a topical probiotic. In contrast, the aqueous probiotic formulation does require that pH and osmolality be adjusted to values that assure a favourable environment for the microorganisms to remain viable. In these two case studies, eight different formulations containing preservatives were tested for live microorganism viability over six weeks after compounding.

Material and methods

The low immunogenic strain of P. acnes (probiotic bacterial active) and phage that attacks pathogenic P. acnes (microbiome editor) were provided by Phi Therapeutics. Two gelled aqueous products were made with the intent of formulating cosmetically elegant products: hydroxyethyl cellulose (HEC) at 1.5% w/w and polyacrylic acid polymer or carbomer (Carbopol 980, Lubrizol) at 0.75% w/w, both titrated with propylene glycol until isosmotic (~285 mOsm/k). Both gels were prepared with the following preservative systems: preservative free, methylparaben (0.1%) and propylparaben (0.02%), phenoxyethanol (1.0%), and potassium sorbate (0.2%). In addition, two solution products were made: an 80:20 water:propylene glycol blend (w/w) and an 80:20 water:ethanol blend (w/w). Both solution blends were considered self-preserving. The pH of all the products were taken, but no pH modifiers were added. Active viability and stability testing were conducted every two weeks after addition of active microorganism by diluting the formulated products to a known concentration of active microorganisms and plating them out. P. acnes concentration was calculated using diluted growth promotion plating and back calculating; the number of phage was calculated by plating the dilutions onto bacterial lawns and looking for the presence of kill zones

MAY 2018

Vaccines and AMR: Strengthening the Fight

Last month’s World Immunization Week, titled “Protected Together, #VaccinesWork”, again highlighted the collective action needed to ensure that every person is protected from vaccine-preventable diseases and encourage people at every level – from donors to the general public – to go further in their efforts to increase immunization coverage for the greater good.

When trying to reduce antimicrobial resistance, how can vaccines help?

Thomas Cueni Thomas Cueni: Vaccines are critical and powerful tools in the fight against AMR and infectious diseases; they not only save lives but reduce the ability of bugs to develop resistance:

They reduce the use of antibiotics by preventing bacterial infections before they occur, thus removing any need to treat the infection. Increasing access to vaccines such as pneumococcal and meningococcal conjugate can decrease infection rates and consequently antibiotic use.

They reduce the prevalence of viral infections, which are often inappropriately treated with antibiotics and can give rise to secondary infections requiring antibiotic treatment. Immunization against viral influenza, for example, can reduce antibiotic use by as much as 64% in vaccinated individuals.

They reduce the number of infections in the population through direct protection of vaccinated individuals and by reducing carriage (the infection of an individual without causing symptoms), thus limiting the spread of infections within a community (herd immunity).

They limit the spread of AMR organisms within communities by reducing the volume of visits to points of care, especially hospitals, which can often be a source of infection.

We reflect the importance of vaccines in the AMR Industry Alliance’s first progress report. The new Alliance of more than 100 biotech, diagnostics, generics and research-based biopharmaceutical companies and trade associations have identified that the full the potential of vaccines has not yet been fully explored.

What needs to be done so that immunization can help reduce antimicrobial resistance (AMR)?

Vaccines can be utilized in the fight against AMR in three ways. First, current vaccination efforts through National Immunization Programs need to be encouraged and universal access to existing vaccines needs to be expanded. Global health efforts under way to eradicate smallpox show that this is a feasible prospect.

Second, immunization programs need to be offered to children and adults alike as part of a life-course approach to preventing disease – one that stresses the importance of vaccination at all stages of life to ward off illness. Adult immunization programs provide a cost-effective approach to promoting health and wellness in older populations and in people with underlying health problems.

Third, the life science industry needs to prioritize the R&D of new vaccines – especially for diseases that pose the biggest threat of drug resistance (the World Health Organization has a priority list of antibiotic-resistant bacteria). There are scientific and commercial challenges in developing new vaccines and more public and private investment, as well as economic and regulatory incentives, is required to overcome these hurdles.

How much of an impact does immunization have today in terms of slowing the antibiotic resistance?

Immunization has a crucial role to play in combatting AMR. Antibiotic resistance has the power to transport us back to a time when minor infections were deadly. Since the 1970s, for example, the typhoid bacteria has been evolving and typhoid, an otherwise vaccine-preventable infectious disease, is becoming increasingly resistant to antibiotics, resulting in the emergence of multi-drug resistant typhoid. Today, vaccines targeting potentially antimicrobial resistant bacteria include: Cholera, Diphtheria, Invasive pneumococcal disease, Meningitis as well as Typhoid fever.

More could be done for example to stop the common misuse of antibiotics against influenza . This is because symptoms are often similar to ones developed with a bacterial infection and the use of point-of-care diagnostics is not systematic. Immunization helps reduce the incidence of influenza infections and, with it, the number of opportunities for misuse of antibiotics. Flu immunization also helps scale back consumption of antibiotics as it prevents the development of bacterial infections associated with influenza (also called “super infection”).

Are vaccines used enough to have an impact on slowing down resistance to antibiotics?

No: a study published in The Lancet [1] has estimated that universal coverage of the pneumococcal vaccine could prevent 11.4 million days of antibiotic use per year in children aged under five while increased immunisation coverage with the rotavirus vaccine could help reduce the over use of antibiotics to treat diarrhoeal disease.

Immunization during the life-course matters more than ever. Expanding access to vaccines is crucial to achieving the Sustainable Development Goals (SDGs), but is also a fundamental strategy in achieving other health priorities such as beating AMR. Universal vaccination and the successful development of new or improved vaccines will be important measures in the long-haul fight against AMR.

What AMR-relevant vaccines are currently in the life-science industry’s pipeline?

Six members of the AMR Industry Alliance are involved in AMR-relevant vaccine R&D, with 13 candidates in active development in the last five years. Some of the relevant bacterial vaccine candidates are in phase I and later of clinical development. These include potential vaccines for tuberculosis, streptococcus pneumoniae, c. difficile, and s.aureas. However, AMR-relevant vaccines face particular scientific and regulatory barriers: their target population is generally much smaller, more vulnerable and contains patients more likely to possess weaker immune systems, preventing the vaccine from being fully effective. This central challenge, combined with the additional regulatory approvals required in some countries, creates a tough economic outlook.

Is there enough R&D in this area considering the scale of the AMR challenge?

Universal vaccination and the successful development of new or improved vaccines are important measures in the long-haul fight against AMR. The AMR Industry Alliance’s first progress report showed that, in 2016, 22 Alliance companies invested at least USD 2 billion in R&D dedicated to AMR-related products. In addition to the 13 clinical bacterial vaccine candidates, the funds cover costs for early-stage R&D, exploring new product classes, ten antibiotics in late-stage clinical development, 18 AMR-relevant diagnostic products, and other preventive therapies. But a majority of Alliance companies viewed R&D incentives as either “promising but with far to go” or “insufficient relative to the challenge”. That notwithstanding, companies involved in vaccines R&D are dedicated to working together as an industry to address AMR and partnering with world leaders and donors to ensure immunization can play its full role in achieving global health security.

What is the role of the life science industry and more specifically the new AMR Industry Alliance in terms of vaccines and reducing antimicrobial resistance?

The Alliance is an industry initiative bringing together over 100 companies from different sectors such as biotech, diagnostics, generics and R&D pharma that pledge to deliver on specific commitments. A key pledge is to foster innovative approaches to using alternatives to antimicrobials and new technologies for diagnosis and vaccines. The Alliance calls for an integrated deployment of vaccines and medicines, diagnostics, antibiotics and other therapies to address the multiple challenges across the continuum of care – from prevention, monitoring and screening to treatment.

While AMR has been top of the global health policy agenda now for some years, has there been enough action and in your opinion what more needs to be done so that vaccines can make a bigger contribution to reducing AMR?

There is a considerable way to go and the scale of antimicrobial resistance has never been so large. Although vaccines are acknowledged as part of the solution, their contribution to the fight against AMR has not been sufficiently explored. The successful development of vaccines and achieving universal vaccination for high burden diseases will be important milestones in that fight. Vaccines should be regarded as a powerful tool in our arsenal to reduce the spread of antibiotic resistance. Not only to pre-emptively reduce the burden of infectious diseases but to reduce the prevalence of resistance by reducing the need for antibiotics.

Expanding access to vaccines should be viewed as key to achieving Universal Health Coverage and most of the SDGs but also fundamental to achieving other health priorities such as combatting AMR.

MAY 2018

Do you know what is contained in a vaccine and why?

In addition to the designated antigen(s), a vaccine contains additives that may include adjuvants, preservatives, stabilizers, conjugating agents and antibiotics.

Adjuvants are designed to enhance the immune response to a vaccine antigen (immunogen) and to allow for use of smaller amounts of antigen. The most commonly used adjuvants in the United States are aluminum salts, such as aluminum hydroxide or aluminum phosphate. Originally, it was thought that aluminum salts acted as a repository for the vaccine antigen, but now it is believed that they also play a role in modulating the inflammatory response.

In the first six months of life, the total amount of aluminum contained in all routinely recommended vaccines is about 4 milligrams (mg). This is about one-half the amount of aluminum received from breast milk and less than one-tenth the amount of aluminum received from regular infant formula during the first six months of life. In over 70 years of use, aluminum salts have proven to be safe and effective.

In 2009, Cervarix (bivalent human papillomavirus vaccine) was licensed in the United States (although it is no longer available in this country). The vaccine contains a novel adjuvant system (AS04) known as monophosphoryl lipid A (a detoxified endotoxin) designed to enhance the immune response. The vaccine has been administered safely to hundreds of thousands of people.

Fluad was licensed by the Food and Drug Administration in November 2015 as the first seasonal influenza vaccine containing a novel adjuvant. Fluad is licensed for people 65 years of age or older but may become available for children. The vaccine contains MF59 as an adjuvant, consisting of an oil-in-water emulsion of squalene oil. Squalene occurs naturally in humans and is one of the major components of skin surface lipids.

Preservatives are added to vaccines to prevent the growth of bacteria or fungi that might cause contamination during use of a multi-dose vial. Four preservatives are currently used in some vaccines: thimerosal, 2-phenoxyethanol, phenol and benzethonium chloride. Some preservatives cannot be used with certain antigens. For example, thimerosal is not used in inactivated polio virus vaccine (IPV) as it may reduce the potency of certain poliovirus serotypes. Instead, 2-phenoxyethanol is used in IPV vaccine formulations.

Stabilizers protect a vaccine from degradation and temperature extremes during manufacture, shipping and storage. They consist of proteins (human serum albumin, gelatin), sugars (sucrose, lactose) or amino acids (glycine, glutamic acid). Because such small quantities of antigen are contained in a vaccine, stabilizers minimize adherence to glass in a vial or syringe. One H. influenzae type b vaccine contains only 10 mcg of polysaccharide antigen per dose. Live vaccines may contain only nanograms of antigen (103-105 viral particles per dose).

Protective immunity against encapsulated bacteria such as Neisseriameningitidis, S.pneumoniae and H.influenzae type b is induced by capsular polysaccharides. When used in inactivated vaccines, capsular polysaccharides are poorly immunogenic and do not result in long-term immunity. Conjugation of capsular polysaccharide to a protein carrier changes the nature of the immune response and converts the polysaccharide to a potent immunogen that can be used effectively in a vaccine. One disadvantage of conjugate vaccines is the complexity of the manufacturing process, resulting in high cost.

Types of proteins used as carriers include tetanus toxoid, diphtheria toxoid and CRM197(naturally occurring nontoxic diphtheria toxin). Recent reports suggest the protein carrier does not need to be directly linked to polysaccharide to enhance the immune response. Fixing the polysaccharide capsular antigen to a protein matrix may enhance a vaccine’s immunogenicity as effectively as a covalent bond (Thanawastien A, et al. Proc Natl Acad Sci USA. 2015;112:e1143-e1151). If proven to be effective, this would allow manufacture of conjugate vaccines in a less complicated process, reduce vaccine cost and enable wider use in developing countries.

Preservatives do not eliminate the risk of contamination, so antimicrobial agents may be added to a vaccine formulation. Antibiotics contained in licensed vaccines include streptomycin, polymyxin B, neomycin and gentamicin. Beta lactam antibiotics are not present in vaccines. Thus, a history of penicillin allergy is not an acceptable reason to avoid immunization.

Vaccines may contain tiny amounts of residual material that remains from the licensed manufacturing process, including yeast protein, formaldehyde and cellular DNA.

It is important to remember that despite their complexity, vaccines are remarkably safe and effective, and adverse reactions to vaccines are monitored constantly. The risk of anaphylaxis to any vaccine is estimated to be one case per 1 million to 2 million vaccine doses administered.

APRIL 2018

High Throughput Screening of Excipient

The Tecan-robotic system is one of the latest developments in the pharmaceutical industry, which facilitates the drug formulation of excipients through its advanced technologies to achieve efficiency.

Compounds should be categorized according to toxicology, bioavailability, pharmacokinetics (PK) and pharmacology profiles at the beginning of the drug development stage. The compound should be dissolved in solution at high concentration levels to achieve therapeutic outcome. The main obstacle involved in drug development is low aqueous solubility.

Current methodologies

Chemical modifications, physical modifications and solvent modifications techniques should be used to facilitate solubility levels. These techniques will be determined by the compounds chemicals propertied, the physical state of the formulation and route of administration. Solvent modifications and carrier systems are used frequently during the formation of liquid formulations as they affect the solvation components of the drugs only instead of the solid-state properties.

Excipients should be utilized to increase the solubility of poorly soluble compounds. The variety of excipients depends on several testing trials using several research orientated methodologies to decide on the preferred excipients. This procedure should be taken into consideration, as it is expensive, time consuming and requires large amounts of material.

Developing a high-throughput screening method

The introduction of a highly throughput screening technique should allow pharmaceuticals to address the difficulties in choosing one or more excipients. A methodology would be formed to reduce the amounts of API used, to ensure that it is commercially viable and effective to achieve results. Creating a platform is required to provide information about a compound’s chemical stability for different solvents and excipients to support decision making.

Numerous experiments were conducted to determine the methodology. The screening list is mainly focused on excipients with different solubilisation mechanisms, which consists of water-soluble organic solvents, non-ionic surfactants, water-insoluble lipids, organic liquids/semi-solids, cyclodextrins, and phospholipids.

The drug delivery system will be determined by the type of excipients used. Orally administered compounds will involve various excipients than injectables. The final concentration of the selected excipients is required to ensure that (GRAS) list of recommended concentrations are safe. The identification of the correct excipient in its individual correct maximum concentration is important, especially for parenteral formulations, because doses that are too high can cause pain, hemolysis, or inflammation.

A new methodology

The high-throughput screening platform involves identifying the solubilization capacity of each excipient for a compound. This in turn should reduce shorten the timeframe involved to identify an excipient by allowing multiple tests to be conducted together.

Six commercially available drugs which feature diverse chemical properties were used to develop this method. 30 excipients were dispensed in 96 well-plates via a fully automated robotic system (Tecan) were used to conduct testing. Three plates were scrutinised to determine each compound. The plate was shaken for 48 hours to achieve equilibrium. The results were compared with solubility measurements performed using a manual shake flask method where 15 mg of powder and 2 mL of excipient were added. The samples were again shaken for 48 hours, centrifuged, and then analyzed by high-performance liquid chromatography (HPLC) to determine solubility and detect any degradation. The measurements were performed in triplicates.

Findings

Results showed that some excipients offer better solubilization capacity than others. Results confirmed that pH-dependent solubility is a beneficial method for ionisable compounds, especially if it can be combined with another solubilizing excipient. The contribution of solid-state barrier to solubilizing a compound appears to be more pronounced at a cut-off level of solid-state properties. Prior to the cut-off point, the solubilization of the compound was more compound specific, which generates requirements to test on a larger set of excipients.

The high-throughput screening technique results proved that using this method for solubility is not numerically different than the previous achieved when using a manual approach. This method can deliver data on the solubilization capacity of compounds in various excipients, while also offering insight into stability.

The high-throughput screening method addresses the issues referring to the manual approaches by being more cost-effective and economical in the use of materials, while efforts are made to achieve these results in three to five days per for each set of compounds.

Conclusion

The development of the platform has generated new opportunities for reduced drug development timeframe and costs. Also, the information gathered during the screening will be beneficial in the advanced stages of formulation development. Excipients will be chosen according to the API’s unique molecular properties, which provides a aster process. This should transform the way developers assess the solubility of any compound, which helps to increase the probability of successful formulation.

MARCH 2018

Flucelvax, the only influenza vaccine developed in the U.S. with cell cultures, may have been 20 percent more effective than standard vaccines developed in eggs this flu season, according to comments made by FDA Commissioner Scott Gottlieb, MD, cited by STAT.

Here are five things to know.

Gottlieb first mentioned the 20 percent figure during a March 8 congressional subcommittee hearing on oversights and investigations regarding the severity of this year’s flu season and the estimated poor performance of the seasonal flu vaccine. The FDA chief confirmed the number in an interview with STAT after the hearing.
“The data aren’t final yet, but I’m comfortable saying that I think it’s going to be about 20 percent improved efficacy for the cell-based vaccine relative to the egg-based vaccines,” Dr. Gottlieb told STAT.

The estimate is derived from FDA analysts who have been examining the medical records of 16 million Medicare beneficiaries to determine whether hospitalization rates vary based upon vaccine type and dose.

Though the FDA analysis can’t break down the data by flu virus type, the dominance of the H3N2strain is likely a key reason the cell-culture-based vaccination may have outperformed the egg-based vaccine.

When vaccines are grown in hen’s eggs, they have to adapt, which can sometimes result in mutations. This seems to be especially true with the H3N2 component. Many experts suspect vaccines grown in cell cultures are less likely to acquire mutations, which may contribute to improved efficacy, according to STAT.

Gottlieb told the congressional committee it was too soon to say whether vaccines grown in cell culture are definitely more effective, arguing the vaccine developed in hen’s eggs actually display more protection against flu in some years. Dr. Gottlieb said more research is needed to know for certain, but if studies confirm the cell-culture vaccine performs better against H3N2, the FDA could “make a recommendation that the H3N2 component has to be produced in a cell-based process and the others can be produced in eggs.”

** This article was written by Brian Zimmerman from Beckers Hospital Review. **

FEBRUARY 2018

Medicine manufacturers ditch batchmethods for continuous production

The widespread trend to move away from batch producing medicine is driving the continuous processing technology market to double in size. Classically, pharma has manufactured medicines in stages, batch by batch ­– which allowed firms to responsively flex output in accordance to demand.

However, recent trends have seen larger pharma firms switch to continuous processing to pick up improvements in productivity. Production steps that are carried out sequentially in a classic batch process are integrated in a continuous process. Active ingredients are produced in compact, closed units, leveraging opportunities for automation and fewer manual interventions.

This method allows manufacturing units to be constantly utilized, so fluctuations in production are reduced and there are opportunities to perform reactions that cannot be run under batch processing.